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Lipodystrophy-associated progeroid syndromes

Abstract

With the exception of HIV-associated lipodystrophy, lipodystrophy syndromes are rare conditions characterized by a lack of adipose tissue, which is not generally recovered. As a consequence, an ectopic deposition of lipids frequently occurs, which usually leads to insulin resistance, atherogenic dyslipidemia, and hepatic steatosis. These disorders include certain accelerated aging syndromes or progeroid syndromes. Even though each of them has unique clinical features, most show common clinical characteristics that affect growth, skin and appendages, adipose tissue, muscle, and bone and, in some of them, life expectancy is reduced. Although the molecular bases of these Mendelian disorders are very diverse and not well known, genomic instability is frequent as a consequence of impairment of nuclear organization, chromatin structure, and DNA repair, as well as epigenetic dysregulation and mitochondrial dysfunction. In this review, the main clinical features of the lipodystrophy-associated progeroid syndromes will be described along with their causes and pathogenic mechanisms, and an attempt will be made to identify which of López-Otín’s hallmarks of aging are present.

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References

  1. Hennekam RCM (2020) The external phenotype of aging. Eur J Med Genet 63:103995. https://doi.org/10.1016/j.ejmg.2020.103995

    Article  PubMed  Google Scholar 

  2. Chen H, Liu O, Chen S, Zhou Y (2022) Aging and mesenchymal stem cells: therapeutic opportunities and challenges in the older group. Gerontology 68:339–352. https://doi.org/10.1159/000516668

    CAS  Article  PubMed  Google Scholar 

  3. López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G (2013) The hallmarks of aging. Cell 153:1194–1217. https://doi.org/10.1016/j.cell.2013.05.039

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  4. Martin GM (2005) Genetic modulation of senescent phenotypes in Homo sapiens. Cell 120:523–532. https://doi.org/10.1016/j.cell.2005.01.031

    CAS  Article  PubMed  Google Scholar 

  5. Hennekam RCM (2020) Pathophysiology of premature aging characteristics in Mendelian progeroid disorders. Eur J Med Genet 63:104028. https://doi.org/10.1016/j.ejmg.2020.104028

    Article  PubMed  Google Scholar 

  6. Araujo-Vilar D, Santini F (2019) Diagnosis and treatment of lipodystrophy: a step-by-step approach. J Endocrinol Invest 42:61–73. https://doi.org/10.1007/s40618-018-0887-z

    CAS  Article  PubMed  Google Scholar 

  7. Guillín-Amarelle C, Fernández-Pombo A, Sánchez-Iglesias S, Araújo-Vilar D (2018) Lipodystrophic laminopathies: diagnostic clues. Nucleus 9:249–260. https://doi.org/10.1080/19491034.2018.1454167

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. Broers JL, Ramaekers FC, Bonne G, Yaou RB, Hutchison CJ (2006) Nuclear lamins: laminopathies and their role in premature ageing. Physiol Rev 86:967–1008. https://doi.org/10.1152/physrev.00047.2005

    CAS  Article  PubMed  Google Scholar 

  9. Ashapkin VV, Kutueva LI, Kurchashova SY, Kireev II (2019) Are there common mechanisms between the Hutchinson-Gilford progeria syndrome and natural aging? Front Genet 10:455. https://doi.org/10.3389/fgene.2019.00455

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. De Sandre-Giovannoli A, Bernard R, Cau P, Navarro C, Amiel J, Boccaccio I, Lyonnet S, Stewart CL, Munnich A, Le Merrer M, Lévy N (2003) Lamin a truncation in Hutchinson-Gilford progeria. Science 300:2055. https://doi.org/10.1126/science.1084125

    Article  PubMed  Google Scholar 

  11. Eriksson M, Brown WT, Gordon LB et al (2003) Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome. Nature 423:293–298. https://doi.org/10.1038/nature01629

    CAS  Article  PubMed  Google Scholar 

  12. Schnabel F, Kornak U, Wollnik B (2021) Premature aging disorders: a clinical and genetic compendium. Clin Genet 99:3–28. https://doi.org/10.1111/cge.13837

    CAS  Article  PubMed  Google Scholar 

  13. Merideth MA, Gordon LB, Clauss S et al (2008) Phenotype and course of Hutchinson-Gilford progeria syndrome. N Engl J Med 358:592–604. https://doi.org/10.1056/NEJMoa0706898

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. Gordon LB, Brown WT, Collins FS (2019) Hutchinson-Gilford progeria syndrome. In: Adam MP, Ardinger HH Pagon SE, Wallace, L. J. H. Bean, Stephens K, Amemiya A (eds) GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2019. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1121/

  15. Novelli G, Muchir A, Sangiuolo F (2002) Mandibuloacral dysplasia is caused by a mutation in LMNA-encoding lamin A/C. Am J Hum Genet 71:426–431. https://doi.org/10.1086/341908

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. Camozzi D, D’Apice MR, Schena E, Cenni V, Columbaro M, Capanni C, Maraldi NM, Squarzoni E, Ortolani M, Novelli G, Lattanzi G (2012) Altered chromatin organization and SUN2 localization in mandibuloacral dysplasia are rescued by drug treatment. Histochem Cell Biol 138:643–651. https://doi.org/10.1007/s00418-012-0977-5

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. Cenni V, D’Apice MR, Garagnani P, Columbaro M, Novelli G, Franceschi C, Lattanzi G (2018) Mandibuloacral dysplasia: a premature ageing disease with aspects of physiological ageing. Ageing Res Rev 42:1–13. https://doi.org/10.1016/j.arr.2017.12.001

    Article  PubMed  Google Scholar 

  18. Chiarini F, Evangelisti C, Cenni V, Fazio A, Paganelli F, Martelli AM, Lattanzi G (2019) The cutting edge: the role of mTOR signaling in laminopathies. Int J Mol Sci 20:847. https://doi.org/10.3390/ijms20040847

    CAS  Article  PubMed Central  Google Scholar 

  19. Jéru I, Nabil A, El-Makkawy G, Lascols O, Vigouroux C, Abdalla E (2021) Two decades after mandibuloacral dysplasia discovery: additional cases and comprehensive view of disease characteristics. Genes (Basel) 12:1508. https://doi.org/10.3390/genes12101508

    CAS  Article  Google Scholar 

  20. Sakka R, Marmouch H, Trabelsi M, Achour A, Golli M, Hannachi I, Kerkeni E, Monastiri K, Maazoul F, M’rad R (2021) Mandibuloacral dysplasia type A in five tunisian patients. Eur J Med Genet 64:104138. https://doi.org/10.1016/j.ejmg.2021.104138

    Article  Google Scholar 

  21. Hussain I, Patni N, Ueda M et al (2018) A novel generalized lipodystrophy-associated progeroid syndrome due to recurrent heterozygous LMNA p. T10I mutation. J Clin Endocrinol Metab 103:1005–1014. https://doi.org/10.1210/jc.2017-02078

    Article  PubMed  Google Scholar 

  22. Garg A, Subramanyam L, Agarwal AK, Simha V, Levine B, D’Apice MR, Novelli G, Crow Y (2009) Atypical progeroid syndrome due to heterozygous missense LMNA mutations. J Clin Endocrinol Metab 94:4971–4983. https://doi.org/10.1210/jc.2009-0472

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. Doubaj Y, De Sandre-Giovannoli A, Esteves-Vieira V, Navarro CL, Elalaoui SC, Tajir M, Lévy N, Sefiani A (2012) An inherited LMNA gene mutation in atypical progeria syndrome. Am J Med Genet A 158A:2881–2887. https://doi.org/10.1002/ajmg.a.35557

    CAS  Article  PubMed  Google Scholar 

  24. Hussain I, Jin RR, Baum HBA et al (2020) Multisystem progeroid syndrome with lipodystrophy, cardiomyopathy, and nephropathy due to an LMNA p.R349W variant. J Endocr Soc 4:bvaa104. https://doi.org/10.1210/jendso/bvaa104

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. Magno S, Ceccarini G, Pelosini C et al (2020) Atypical progeroid syndrome and partial lipodystrophy due to LMNA gene p.R349W mutation. J Endocr Soc 4:bvaa108. https://doi.org/10.1210/jendso/bvaa108

    Article  PubMed  PubMed Central  Google Scholar 

  26. Agarwal AK, Fryns JP, Auchus RJ, Garg A (2003) Zinc metalloproteinase, ZMPSTE24, is mutated in mandibuloacral dysplasia. Hum Mol Genet 12:1995–2001. https://doi.org/10.1093/hmg/ddg213

    CAS  Article  PubMed  Google Scholar 

  27. Hitzert MM, van der Crabben SN, Baldewsingh G, Ploos van Amstel HK, van den Wijngaard A, van Ravenswaaij-Arts CMA, Zijlmans CWR (2019) Mandibuloacral dysplasia type B (MADB): a cohort of eight patients from Suriname with a homozygous founder mutation in ZMPSTE24 (FACE1), clinical diagnostic criteria and management guidelines. Orphanet J Rare Dis 14:294. https://doi.org/10.1186/s13023-019-1269-0

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. Agarwal AK, Zhou XJ, Hall RK, Nicholls K, Bankier A, Van Esch H, Fryns JP, Garg A (2006) Focal segmental glomerulosclerosis in patients with mandibuloacral dysplasia owing to ZMPSTE24 deficiency. J Investig Med 54:208–213. https://doi.org/10.2310/6650.2006.05068

    Article  PubMed  Google Scholar 

  29. Puente XS, Quesada V, Osorio FG et al (2011) Exome sequencing and functional analysis identifies BANF1 mutation as the cause of a hereditary progeroid syndrome. Am J Hum Genet 88:650–6. https://doi.org/10.1016/j.ajhg.2011.04.010

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. Rose M, Bai B, Tang M, Cheong CM, Beard S, Burgess JT, Adams MN, O’Byrne KJ, Richard DJ, Gandhi NS, Bolderson E (2021) The impact of rare human variants on barrier-to-auto-integration factor 1 (Banf1) structure and function. Front Cell Dev Biol 9:775441. https://doi.org/10.3389/fcell.2021.775441

    Article  PubMed  PubMed Central  Google Scholar 

  31. Cabanillas R, Cadiñanos J, Villameytide JAF, Pérez M, Longo J, Richard JM, Alvarez R, Durán NS, Illán R, González DJ, López-Otín C (2011) Néstor-Guillermo progeria syndrome: a novel premature aging condition with early onset and chronic development caused by BANF1 mutations. Am J Med Genet Part A 155:2617–2625. https://doi.org/10.1002/ajmg.a.34249

    CAS  Article  Google Scholar 

  32. Fisher HG, Patni N, Scheuerle AE (2020) An additional case of Néstor-Guillermo progeria syndrome diagnosed in early childhood. Am J Med Genet A 182:2399–2402. https://doi.org/10.1002/ajmg.a.61777

    CAS  Article  PubMed  Google Scholar 

  33. Lord CJ, Ashworth A (2012) The DNA damage response and cancer therapy. Nature 481:287–294. https://doi.org/10.1038/nature10760

    CAS  Article  PubMed  Google Scholar 

  34. Lu H, Davis AJ (2021) Human RecQ helicases in DNA double-strand break repair. Front Cell Dev Biol 9:640755. https://doi.org/10.3389/fcell.2021.640755

    Article  PubMed  PubMed Central  Google Scholar 

  35. Gudmundsrud R, Skjånes TH, Gilmour BC, Caponio D, Lautrup S, Fang EF (2021) Crosstalk among DNA damage, mitochondrial dysfunction, impaired mitophagy, stem cell attrition, and senescence in the accelerated ageing disorder Werner syndrome. Cytogenet Genome Res 161:297–304. https://doi.org/10.1159/000516386

    CAS  Article  PubMed  Google Scholar 

  36. Zhang W, Li J, Suzuki K et al (2015) Aging stem cells. A Werner syndrome stem cell model unveils heterochromatin alterations as a driver of human aging. Science 348:1160–1163. https://doi.org/10.1126/science.aaa1356

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  37. Ishikawa N, Nakamura K, Izumiyama-Shimomura N et al (2011) Accelerated in vivo epidermal telomere loss in Werner syndrome. Aging (Albany NY) 3:417–429. https://doi.org/10.18632/aging.100315

    Article  Google Scholar 

  38. Lauper JM, Krause A, Vaughan TL, Monnat RJ Jr (2013) Spectrum and risk of neoplasia in Werner syndrome: a systematic review. PLoS ONE 8:e59709. https://doi.org/10.1371/journal.pone.0059709

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  39. Goh KJ, Chen JH, Rocha N, Semple RK, RK, (2020) Human pluripotent stem cell-based models suggest preadipocyte senescence as a possible cause of metabolic complications of Werner and Bloom Syndromes. Sci Rep 10:7490. https://doi.org/10.1038/s41598-020-64136-8

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  40. Maciejczyk M, Mikoluc B, Pietrucha B, Heropolitanska-Pliszka E, Pac M, Motkowski R, Car H (2017) Oxidative stress, mitochondrial abnormalities and antioxidant defense in Ataxia-telangiectasia, Bloom syndrome and Nijmegen breakage syndrome. Redox Biol 11:375–383. https://doi.org/10.1016/j.redox.2016.12.030

    CAS  Article  PubMed  Google Scholar 

  41. Cunniff C, Bassetti JA, Ellis NA (2017) Bloom’s syndrome: clinical spectrum, molecular pathogenesis, and cancer predisposition. Mol Syndromol 8:4–23. https://doi.org/10.1159/000452082

    CAS  Article  PubMed  Google Scholar 

  42. Tiwari V, Wilson DM 3rd (2019) DNA damage and associated DNA repair defects in disease and premature aging. Am J Hum Genet 105:237–257. https://doi.org/10.1016/j.ajhg.2019.06.005

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  43. Pascucci B, Fragale A, Marabitti V, Leuzzi G, Calcagnile AS, Parlanti E, Franchitto A, Dogliotti E, D’Errico M (2018) CSA and CSB play a role in the response to DNA breaks. Oncotarget 9:11581–11591. https://doi.org/10.18632/oncotarget.24342

  44. Batenburg NL, Walker JR, Noordermeer SM, Moatti N, Durocher D, Zhu XD (2017) ATM and CDK2 control chromatin remodeler CSB to inhibit RIF1 in DSB repair pathway choice. Nat Commun 8:1921–1921. https://doi.org/10.1038/s41467-017-02114-x

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  45. Tiwari V, Baptiste BA, Okur MN, Bohr VA (2021) Current and emerging roles of Cockayne syndrome group B (CSB) protein. Nucleic Acids Res 49:2418–2434. https://doi.org/10.1093/nar/gkab085

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  46. Karikkineth AC, Scheibye-Knudsen M, Fivenson E, Croteau DL, Bohr VA (2017) Cockayne syndrome: clinical features, model systems and pathways. Ageing Res Rev 33:3–17. https://doi.org/10.1016/j.arr.2016.08.002

    CAS  Article  PubMed  Google Scholar 

  47. Lessel D, Vaz B, Halder S et al (2014) Mutations in SPRTN cause early onset hepatocellular carcinoma, genomic instability and progeroid features. Nat Genet 46:1239–1244. https://doi.org/10.1038/ng.3103

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  48. Ruggiano A, Ramadan K (2021) The trinity of SPRTN protease regulation. Trends Biochem Sci 46:2–4. https://doi.org/10.1016/j.tibs.2020.10.007

    CAS  Article  PubMed  Google Scholar 

  49. Ruijs MWG, van Andel RNJ, Oshima J, Madan K, Nieuwint AWM, Aalfs CM. Atypical progeroid syndrome: an unknown helicase gene defect? Am J Med Genet A 116A:295–9. https://doi.org/10.1002/ajmg.a.10730.

  50. Murdocca M, Spitalieri P, De Masi C et al (2021) Functional analysis of POLD1 p.ser605del variant: the aging phenotype of MDPL syndrome is associated with an impaired DNA repair capacity. Aging (Albany NY) 13:4926–4945. https://doi.org/10.18632/aging.202680

  51. Weedon MN, Ellard S, Brindle MJ et al (2013) An in-frame deletion at the polymerase active site of POLD1 causes a multisystem disorder with lipodystrophy. Nat Genet 45:947–950. https://doi.org/10.1038/ng.2670

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  52. Murdocca M, Spitalieri P, Cappello A, Colasuonno F, Moreno S, Candi E, D’Apice MR, Novelli G, Sangiuolo F (2022) Mitochondrial dysfunction in mandibular hypoplasia, deafness and progeroid features with concomitant lipodystrophy (MDPL) patients. Aging (Albany NY). 14:1651–1664. https://doi.org/10.18632/aging.203910

  53. Jay AM, Conway RL, Thiffault I, Saunders C, Farrow E, Adams J, Toriello HV (2016) Neonatal progeriod syndrome associated with biallelic truncating variants in POLR3A. Am J Med Genet A 170:3343–3346. https://doi.org/10.1002/ajmg.a.37960

    CAS  Article  PubMed  Google Scholar 

  54. Tiku V (2018) Antebi A (2018) Nucleolar function in lifespan regulation. Trends Cell Biol 28:662–672. https://doi.org/10.1016/j.tcb.2018.03.007

    CAS  Article  PubMed  Google Scholar 

  55. Paolacci S, Bertola D, Franco J, Mohammed S, Tartaglia M, Wollnik B, Hennekam RC (2017) Wiedemann-Rautenstrauch syndrome: a phenotype analysis. Am J Med Genet A 173:1763–1772. https://doi.org/10.1002/ajmg.a.38246

    CAS  Article  PubMed  Google Scholar 

  56. Báez-Becerra C, Valencia-Rincón E, Velásquez-Méndez K, Ramírez-Suárez NJ, Guevara C, Sandoval-Hernandez A, Arboleda-Bustos CE, Olivos-Cisneros L, Gutiérrez-Ospina G, Arboleda H, Arboleda G (2020) Nucleolar disruption, activation of P53 and premature senescence in POLR3A-mutated Wiedemann-Rautenstrauch syndrome fibroblasts. Mech Ageing Dev 192:111360. https://doi.org/10.1016/j.mad.2020.111360

    CAS  Article  PubMed  Google Scholar 

  57. Traba J, Del Arco A, Duchen MR, Szabadkai G, Satrústegui J (2012) SCaMC-1 promotes cancer cell survival by desensitizing mitochondrial permeability transition via ATP/ADP-mediated matrix Ca(2+) buffering. Cell Death Differ 19:650–660. https://doi.org/10.1038/cdd.2011.139

    CAS  Article  PubMed  Google Scholar 

  58. Ehmke N, Graul-Neumann L, Smorag L et al (2017) De novo mutations in SLC25A24 cause a craniosynostosis syndrome with hypertrichosis, progeroid appearance, and mitochondrial Dysfunction. Am J Hum Genet 101:833–843. https://doi.org/10.1016/j.ajhg.2017.09.016

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  59. Writzl K, Maver A, Lidija Kovačič L et al (2017) De novo mutations in SLC25A24 cause a disorder characterized by early aging, bone dysplasia, characteristic face, and early demise. Am J Hum Genet 101:844–855. https://doi.org/10.1016/j.ajhg.2017.09.017

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  60. Armstrong LC, Saenz AJ, Bornstein P (1999) Metaxin 1 interacts with metaxin 2, a novel related protein associated with the mammalian mitochondrial outer membrane. J Cell Biochem 74:11–22

    CAS  Article  Google Scholar 

  61. Elouej S, Harhouri K, Mao ML et al (2020) Loss of MTX2 causes mandibuloacral dysplasia and links mitochondrial dysfunction to altered nuclear morphology. Nat Commun 11:4589. https://doi.org/10.1038/s41467-020-18146-9

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  62. Fischer-Zirnsak B, Escande-Beillard N, Ganesh J et al (2015) Recurrent de novo mutations affecting residue Arg138 of pyrroline-5-carboxylate synthase cause a progeroid form of autosomal-dominant cutis laxa. Am J Hum Genet 97:483–492. https://doi.org/10.1016/j.ajhg.2015.08.001

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  63. Reversade B, Escande-Beillard N, Dimopoulos A et al (2009) Mutations in PYCR1 cause cutis laxa with progeroid features. Nat Genet 41(9):1016–1021. https://doi.org/10.1038/ng.413

    CAS  Article  PubMed  Google Scholar 

  64. Coutelier M, Goizet C, Durr A et al (2015) Alteration of ornithine metabolism leads to dominant and recessive hereditary spastic paraplegia. Brain 138:2191–2205. https://doi.org/10.1093/brain/awv143

    Article  PubMed  PubMed Central  Google Scholar 

  65. Thauvin-Robinet C, Auclair M, Diploma L et al (2013) PIK3R1 mutations cause syndromic insulin resistance with lipoatrophy. Am J Hum Genet 93:141–149. https://doi.org/10.1016/j.ajhg.2013.05.019

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  66. Engelman JA, Luo J, Cantley LC (2006) The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet 7:606–619. https://doi.org/10.1038/nrg1879

    CAS  Article  PubMed  Google Scholar 

  67. Mukherjee A, Rotwein P (2012) Selective signaling by Akt1 controls osteoblast differentiation and osteoblast-mediated osteoclast development. Mol Cell Biol 32:490–500. https://doi.org/10.1128/MCB.06361-11

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  68. Donlon TA, Chen R, Masaki KH, Willcox BJ, Morris BJ (2022) Association with longevity of phosphatidylinositol 3-kinase regulatory subunit 1 gene variants stems from protection against mortality risk in men with cardiovascular disease. Gerontology 68:162–170. https://doi.org/10.1159/000515390

    CAS  Article  PubMed  Google Scholar 

  69. Chudasama KK, Winnay J, Johansson S et al (2013) SHORT syndrome with partial lipodystrophy due to impaired phosphatidylinositol 3 kinase signaling. Am J Hum Genet 93:150–157. https://doi.org/10.1016/j.ajhg.2013.05.023

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  70. Bredrup C, Stokowy T, McGaughran J et al (2019) A tyrosine kinase-activating variant Asn666Ser in PDGFRB causes a progeria-like condition in the severe end of Penttinen syndrome. Eur J Hum Genet 27:574–581. https://doi.org/10.1038/s41431-018-0323-z

    CAS  Article  PubMed  Google Scholar 

  71. Lemmon MA, Schlessinger J (2010) Cell signaling by receptor tyrosine kinases. Cell 141:1117–1134. https://doi.org/10.1016/j.cell.2010.06.011

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  72. Andrae J, Gallini R, Betsholtz C (2008) Role of platelet-derived growth factors in physiology and medicine. Genes Dev 22:1276–1312. https://doi.org/10.1101/gad.1653708

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  73. Aggarwal B, Correa ARE, Gupta N, Jana M, Kabra M (2022) First case report of Penttinen syndrome from India. Am J Med Genet A 188:683–687. https://doi.org/10.1002/ajmg.a.62558

    Article  PubMed  Google Scholar 

  74. Masotti A, Uva P, Davis-Keppel L et al (2015) Keppen-Lubinsky syndrome is caused by mutations in the inwardly rectifying K+ channel encoded by KCNJ6. Am J Hum Genet 96:295–300. https://doi.org/10.1016/j.ajhg.2014.12.011

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  75. Cooper A, Grigoryan G, Guy-David L, Tsoory MM, Chen A, Reuveny E (2012) Trisomy of the G protein-coupled K+ channel gene, Kcnj6, affects reward mechanisms, cognitive functions, and synaptic plasticity in mice. Proc Natl Acad Sci 109:2642–2647. https://doi.org/10.1073/pnas.1109099109

    Article  PubMed  PubMed Central  Google Scholar 

  76. Kessi M, Chen B, Peng J, Tang Y, Olatoutou E, He F, Yang L, Yin F (2020) Intellectual disability and potassium channelopathies: a systematic review. Front Genet 11:614. https://doi.org/10.3389/fgene.2020.00614

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  77. Sundelacruz S, Levin M, Kaplan DL (2008) Membrane potential controls adipogenic and osteogenic differentiation of mesenchymal stem cells. PLoS ONE 3:e3737. https://doi.org/10.1371/journal.pone.0003737

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  78. Horvath GA, Zhao Y, Tarailo-Graovac M et al (2018) Gain-of-function KCNJ6 mutation in a severe hyperkinetic movement disorder phenotype. Neuroscience 384:152–164. https://doi.org/10.1016/j.neuroscience.2018.05.031

    CAS  Article  PubMed  Google Scholar 

  79. Xu L, Jensen H, Johnston JJ et al (2018) Recurrent, activating variants in the receptor tyrosine kinase DDR2 cause Warburg-Cinotti syndrome. Am J Hum Genet 103:976–983. https://doi.org/10.1016/j.ajhg.2018.10.013

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  80. Warburg M, Ullman S, Jensen H, Pedersen H, Kobayashi T, Russell B, Tranebjaerg L, Richard G, Brøndum-Nielsen K (2006) Blepharophimosis, corneal vascularization, deafness, and acroosteolysis: a “new” syndrome? Am J Med Genet A 140:2709–2713. https://doi.org/10.1002/ajmg.a.31543

    Article  PubMed  Google Scholar 

  81. Cinotti E, Ferrero G, Paparo F, Papadia M, Faravelli F, Rongioletti F, Traverso C, Di Maria E. Arthropathy, osteolysis, keloids, relapsing conjunctival pannus and gingival overgrowth: a variant of polyfibromatosis? Am J Med Genet A 161A:1214–20. https://doi.org/10.1002/ajmg.a.35908

  82. Graul-Neumann LM, Kienitz T, Robinson PN, Baasanjav S, Karow B, Gillessen-Kaesbach G, Fahsold R, Schmidt H, Hoffmann K, Passarge E (2010) Marfan syndrome with neonatal progeroid syndrome-like lipodystrophy associated with a novel frameshift mutation at the 3’ terminus of the FBN1-gene. Am J Med Genet A 152A:2749–2755. https://doi.org/10.1002/ajmg.a.33690

    CAS  Article  PubMed  Google Scholar 

  83. Jensen SA, Handford PA (2016) New insights into the structure, assembly and biological roles of 10–12 nm connective tissue microfibrils from fibrillin-1 studies. Biochem J 473:827–838. https://doi.org/10.1042/BJ20151108

    CAS  Article  PubMed  Google Scholar 

  84. Muthu ML, Reinhardt DP (2020) Fibrillin-1 and fibrillin-1-derived asprosin in adipose tissue function and metabolic disorders. J Cell Commun Signal 14:159–173. https://doi.org/10.1007/s12079-020-00566-3

    Article  PubMed  PubMed Central  Google Scholar 

  85. Lin M, Liu Z, Liu G et al (2020) Genetic and molecular mechanism for distinct clinical phenotypes conveyed by allelic truncating mutations implicated in FBN1. Mol Genet Genomic Med 8:e1023. https://doi.org/10.1002/mgg3.1023

    Article  PubMed  Google Scholar 

  86. Buchan JG, Alvarado DM, Haller GE et al (2014) Rare variants in FBN1 and FBN2 are associated with severe adolescent idiopathic scoliosis. Hum Mol Genet 23:5271–5282. https://doi.org/10.1093/hmg/ddu224

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  87. Romere C, Duerrschmid C, Bournat J et al (2016) Asprosin, a fasting-induced glucogenic protein hormone. Cell 165:566–579. https://doi.org/10.1016/j.cell.2016.02.063

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  88. Verzaro R, Minervini M, Gridelli B (2008) Toward “no age limit” for liver transplant donors. Transplantation 85:1869–1870. https://doi.org/10.1097/TP.0b013e31817b00c2

    Article  PubMed  Google Scholar 

  89. Scaffidi P, Misteli T (2008) Lamin A-dependent misregulation of adult stem cells associated with accelerated ageing. Nat Cell Biol 10:452–459. https://doi.org/10.1038/ncb1708

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  90. Tu J, Wan C, Zhang F, Cao L, Law PWN, Tian Y, Lu G, Rennert OM, Chan WY, Cheung HH (2020) Genetic correction of Werner syndrome gene reveals impaired pro-angiogenic function and HGF insufficiency in mesenchymal stem cells. Aging Cell 19:e13116. https://doi.org/10.1111/acel.13116

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  91. Cheung HH, Liu X, Canterel-Thouennon L, Li L, Edmonson C, Rennert OM (2014) Telomerase protects werner syndrome lineage-specific stem cells from premature aging. Stem Cell Rep 2:534–546. https://doi.org/10.1016/j.stemcr.2014.02.006

    CAS  Article  Google Scholar 

  92. Infante A, Rodríguez CI (2021) Cell and cell-free therapies to counteract human premature and physiological aging: MSCs come to light. J Pers Med 11:1043. https://doi.org/10.3390/jpm11101043

    Article  PubMed  PubMed Central  Google Scholar 

  93. Guo Z, He Y, Wang S, Zhang A, Zhao P, Gao C, Cao B (2011) Various effects of hepatoma-derived growth factor on cell growth, migration and invasion of breast cancer and prostate cancer cells. Oncol Rep 26(2):511–517. https://doi.org/10.3892/or.2011.1295

    CAS  Article  PubMed  Google Scholar 

  94. You L, Wang Z, Li H, Shou J, Jing Z, Xie J, Sui X, Pan H, Han W (2015) The role of STAT3 in autophagy. Autophagy 11:729–739. https://doi.org/10.1080/15548627.2015.1017192

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  95. Cohen PR, Tomson BN, Elkin SK, Marchlik E, Carter JL, Razelle Kurzrock (2016) Genomic portfolio of Merkel cell carcinoma as determined by comprehensive genomic profiling: implications for targeted therapeutics. Oncotarget 7:23454–67. https://doi.org/10.18632/oncotarget.8032

  96. Gordon LB, Shappell H, Massaro J, D’Agostino RB Sr, Brazier J, Campbell SE, Kleinman ME, Kieran MW (2018) Association of lonafarnib treatment vs no treatment with mortality rate in patients with Hutchinson-Gilford progeria syndrome. JAMA 319:1687–1695. https://doi.org/10.1001/jama.2018.3264

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  97. Araujo-Vilar D, Sánchez-Iglesias S, Guillín-Amarelle C et al (2015) Recombinant human leptin treatment in genetic lipodystrophic syndromes: the long-term Spanish experience. Endocrine 49:139–147. https://doi.org/10.1007/s12020-014-0450-4

    CAS  Article  PubMed  Google Scholar 

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Acknowledgements

This work was supported by the Instituto de Salud Carlos III and the European Regional Development Fund (ERDF (grant number PI081449), and an intramural grant from the Xunta de Galicia (GPC2014/036, ED341b 2017/19, ED431B 2020/37). A.F.-P. is a Rio Hortega researcher (ISCIII; CM20/00155). S.S.-I. was awarded a Research Fellowship from the Asociación Española de Familiares y Afectados de Lipodistrofias (AELIP).

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Correspondence to David Araújo-Vilar.

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D.A-V has received fees for talks and CME from Amryt Pharma; the other authors have no conflicts of interest to declare.

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Araújo-Vilar, D., Fernández-Pombo, A., Cobelo-Gómez, S. et al. Lipodystrophy-associated progeroid syndromes. Hormones (2022). https://doi.org/10.1007/s42000-022-00386-7

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Keywords

  • Lipodystrophy
  • Early aging
  • Progeria
  • Laminopathies
  • Dysmorphoplogy
  • Genome instability